PDF(Pubmed)
Abstract：
Non-alcoholic steatohepatitis (NASH) is a hepatocyte inflammation based on hepatocellular steatosis, yet there is no effective drug treatment. Atherosclerosis (AS) is caused by lipid deposition in the endothelium, which can lead to various cardiovascular diseases. NASH and AS share common risk factors, and NASH can also elevate the risk of AS, causing a higher morbidity and mortality rate for atherosclerotic heart disease. Therefore, timely detection and diagnosis of NASH and AS are particularly important. In this study, differential gene expression analysis and weighted gene co-expression network analysis were performed on the AS (GSE100927) and NASH (GSE89632) datasets to obtain common crosstalk genes, respectively. Then, candidate Hub genes were screened using four topological algorithms and externally validated in the GSE43292 and GSE63067 datasets to obtain Hub genes. Furthermore, immune infiltration analysis and gene set variation analysis were performed on the Hub genes to explore the underlying mechanisms. The DGIbd database was used to screen candidate drugs for AS and NASH. Finally, a NASH model was constructed using free fatty acid-induced human L02 cells, an AS model was constructed using lipopolysaccharide-induced HUVECs, and a co-morbidity model was constructed using L02 cells and HUVECs to verify Hub gene expression. The result showed that a total of 113 genes common to both AS and NASH were identified as crosstalk genes, and enrichment analysis indicated that these genes were mainly involved in the regulation of immune and metabolism-related pathways. 28 candidate Hub genes were screened according to four topological algorithms, and CXCL9, IL2RB, and SPP1 were identified as Hub genes after in vitro experiments and external dataset validation. The ROC curves and SVM modeling demonstrated the good diagnostic efficacy of these three Hub genes. In addition, the Hub genes are strongly associated with immune cell infiltration, especially macrophages and γ-δ T cell infiltration. Finally, five potential therapeutic drugs were identified. has-miR-185 and hsa-miR-335 were closely related to AS and NASH. This study demonstrates that CXCL9, IL2RB, and SPP1 may serve as potential biomarkers for the diagnosis of the co-morbidity patterns of AS and NASH and as potential targets for drug therapy.
摘要：
非酒精性脂肪性肝炎（NASH）是基于肝细胞脂肪变性的肝细胞炎症，然而，没有有效的药物治疗。动脉粥样硬化（AS）是由内皮中的脂质沉积引起的，会导致各种心血管疾病。NASH和AS具有共同的风险因素，NASH也可以提高AS的风险，导致动脉粥样硬化性心脏病的发病率和死亡率更高。因此,及时检测和诊断NASH和AS尤为重要。在这项研究中,在AS(GSE100927)和NASH(GSE89632)数据集上进行差异基因表达分析和加权基因共表达网络分析，以获得常见的串扰基因，分别。然后，使用四种拓扑算法筛选候选Hub基因，并在GSE43292和GSE63067数据集中进行外部验证，以获得Hub基因。此外，对Hub基因进行免疫浸润分析和基因集变异分析，探讨其潜在机制。DGIbd数据库用于筛选AS和NASH的候选药物。最后,使用游离脂肪酸诱导的人L02细胞构建NASH模型，使用脂多糖诱导的HUVECs构建AS模型，并使用L02细胞和HUVECs构建合并症模型以验证Hub基因表达。结果表明，共有113个AS和NASH共同的基因被鉴定为串扰基因，和富集分析表明，这些基因主要参与免疫和代谢相关通路的调节。根据四种拓扑算法筛选了28个候选Hub基因，和CXCL9、IL2RB、和SPP1在体外实验和外部数据集验证后被鉴定为Hub基因。ROC曲线和SVM建模证明了这三个Hub基因的良好诊断功效。此外,Hub基因与免疫细胞浸润密切相关，尤其是巨噬细胞和γ-δT细胞浸润。最后,确定了5种潜在的治疗药物.hsa-miR-185和hsa-miR-335与AS和NASH密切相关。本研究表明CXCL9、IL2RB、和SPP1可作为AS和NASH合并症模式诊断的潜在生物标志物,也可作为药物治疗的潜在靶点.
